Pekka Jylhä

Major depressive disorder and white matter abnormalities: A diffusion tensor imaging study with tract-based spatial statistics

BACKGROUND A few diffusion tensor imaging (DTI) studies have shown abnormalities in areas of white matter tracts involved in mood regulation in geriatric depressive patients, using a region-of-interest technique. A voxel-based morphometry DTI study of young depressive patients reported similar results. In this study, we explored the structure of the white matter of the whole brain with DTI in middle-aged major depressive disorder (MDD) patients, using novel tract-based spatial statistics. METHODS Sixteen MDD patients and 20 controls underwent DTI. An automated tract-based spatial method (TBSS) was used to analyze the scans. RESULTS Compared with controls, the MDD patients showed a trend for lower values of fractional anisotropy (FA) in the left sagittal stratum, and suggestive decreased FA in the right cingulate cortex and posterior body of corpus callosum. Regressing out the duration and severity of disorder in the model did not change the finding in the sagittal stratum, but dissipated the decrease of FA in latter regions. LIMITATIONS Possibly by reason of a relatively small study sample for a TBSS, the results are suggestive, and should be replicated in further studies. CONCLUSIONS A novel observer-independent DTI method showed decreased FA in the middle-aged MDD patients in white matter regions that have previously connected to the emotional regulation. Lower FA might imply underlying structural abnormalities that contribute to the dysfunction detected in the limbic-cortical network of depressive patients.

P2RX7 gene is associated consistently with mood disorders and predicts clinical outcome in three clinical cohorts

We investigated the effect of nine candidate genes on risk for mood disorders, hypothesizing that predisposing gene variants not only elevate the risk for mood disorders but also result in clinically significant differences in the clinical course of mood disorders. We genotyped 178 DSM‐IV bipolar I and II and 272 major depressive disorder patients from three independent clinical cohorts carefully diagnosed with semistructured interviews and prospectively followed up with life charts for a median of 60 (range 6–83) months. Healthy control subjects (n = 1322) were obtained from the population‐based national Health 2000 Study. We analyzed 62 genotyped variants within the selected genes (BDNF, NTRK2, SLC6A4, TPH2, P2RX7, DAOA, COMT, DISC1, and MAOA) against the presence of mood disorder, and in post‐hoc analyses, specifically against bipolar disorder or major depressive disorder. Estimates for time ill were based on life charts. The P2RX7 gene variants rs208294 and rs2230912 significantly elevated the risk for a familial mood disorder (OR = 1.35, P = 0.0013, permuted P = 0.06, and OR = 1.44, P = 0.0031, permuted P = 0.17, respectively). The results were consistent in all three cohorts. The same risk alleles predicted more time ill in all cohorts (OR 1.3, 95% CI 1.1–1.6, P = 0.0069 and OR 1.7, 95% CI 1.3–2.3, P = 0.0002 with rs208294 and rs2230912, respectively), so that homozygous carriers spent 12 and 24% more time ill. P2RX7 and its risk alleles predisposed to mood disorders consistently in three independent clinical cohorts. The same risk alleles resulted in clinically significant differences in outcome of patients with major depressive and bipolar disorder.

Temperament and character traits predict future burden of depression

BACKGROUND Personality traits are associated with depressive symptoms and psychiatric disorders. Evidence for their value in predicting accumulation of future dysphoric episodes or clinical depression in long-term follow-up is limited, however. METHODS Within a 15-year longitudinal study of a general-population cohort (N=751), depressive symptoms were measured at four time points using Beck׳s Depression Inventory. In addition, 93 primary care patients with DSM-IV depressive disorders and 151 with bipolar disorder, diagnosed with SCID-I/P interviews, were followed for five and 1.5 years with life-chart methodology, respectively. Generalized linear regression models were used to predict future number of dysphoric episodes and total duration of major depressive episodes. Baseline personality was measured by the Temperament and Character Inventory (TCI). RESULTS In the general-population sample, one s.d. lower Self-directedness predicted 7.6-fold number of future dysphoric episodes; for comparison, one s.d. higher baseline depressive symptoms increased the episode rate 4.5-fold. High Harm-avoidance and low Cooperativeness also implied elevated dysphoria rates. Generally, personality traits were poor predictors of depression for specific time points, and in clinical populations. Low Persistence predicted 7.5% of the variance in the future accumulated depression in bipolar patients, however. LIMITATIONS Degree of recall bias in life charts, limitations of statistical power in the clinical samples, and 21-79% sample attrition (corrective imputations were performed). CONCLUSION TCI predicts future burden of dysphoric episodes in the general population, but is a weak predictor of depression outcome in heterogeneous clinical samples. Measures of personality appear more useful in detecting risk for depression than in clinical prediction.

Influence of personality on objective and subjective social support among patients with major depressive disorder: a prospective study

Personality and social support (SS) influence risk for depression and modify its outcome through multiple pathways. The impact of personality dimensions neuroticism and extraversion on SS among patients with major depressive disorder (MDD) has been little studied. In the Vantaa Depression Study, we assessed neuroticism and extraversion with the Eysenck Personality Inventory, objective SS with the Interview Measure of Social Relationships, and subjective SS with the Perceived Social Support Scale-Revised at baseline, at 6 and 18 months among 193 major depressive disorder patients diagnosed according to the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DMS-IV). At all time-points, low neuroticism and high extraversion associated significantly with between-subject differences in levels of objective and subjective SS. Lower neuroticism (&bgr; = 0.213, p = 0.003) and higher extraversion (&bgr; = 0.159, p = 0.038) predicted greater within-subject change of subjective, but not objective SS. Thus, neuroticism and extraversion associated with the size of objective and subjective SS and predicted change of subjective SS. Modification of subjective SS, particularly, may indirectly influence future vulnerability to depression.

Temperament, character and suicide attempts in unipolar and bipolar mood disorders

OBJECTIVE Personality features may indicate risk for both mood disorders and suicidal acts. How dimensions of temperament and character predispose to suicide attempts remains unclear. METHOD Patients (n = 597) from 3 prospective cohort studies (Vantaa Depression Study [VDS], Jorvi Bipolar Study [JoBS], and Vantaa Primary Care Depression Study [PC-VDS]) were interviewed at baseline, at 18 months, and, in VDS and PC-VDS, at 5 years (1997-2003). Personality was measured with the Temperament and Character Inventory-Revised (TCI-R), and follow-up time spent in major depressive episodes (MDEs) as well as lifetime (total) and prospectively ascertained suicide attempts during the follow-up were documented. RESULTS Overall, 219 patients had 718 lifetime suicide attempts; 88 patients had 242 suicide attempts during the prospective follow-up. The numbers of both the total and prospective suicide attempts were associated with low self-directedness (β = -0.266, P = .004, and β = -0.294, P < .001, respectively) and high self-transcendence (β = 0.287, P = .002, and β = 0.233, P = .002, respectively). Total suicide attempts were linked to high novelty seeking (β = 0.195, P = .05). Prospective, but not total, suicide attempts were associated with high harm avoidance (β = 0.322, P < .001, and β = 0.184, P = .062, respectively) and low reward dependence (β = -0.274, P < .001, and β = -0.134, P = .196, respectively), cooperativeness (β = -0.181, P = .005, and β = -0.096, P = .326, respectively), and novelty seeking (β = -0.137, P = .047). No association remained significant when only prospective suicide attempts during MDEs were included. After adjustment was made for total time spent in MDEs, only high persistence predicted suicide attempts (β = 0.190, P < .05). Formal mediation analyses of harm avoidance and self-directedness on prospectively ascertained suicide attempts indicated significant mediated effect through time at risk in MDEs, but no significant direct effect. CONCLUSIONS Among mood disorder patients, suicide attempt risk is associated with temperament and character dimensions. However, their influence on predisposition to suicide attempts is likely to be mainly indirect, mediated by more time spent in depressive episodes.

Temperament, character and personality disorders

OBJECTIVE To study, whether temperament and character remain stable over time and whether they differ between patients with and without personality disorder (PD) and between patients with specific PDs. METHODS Patients with (n=225) or without (n=285) PD from Jorvi Bipolar Study, Vantaa Depression Study (VDS) and Vantaa Primary Care Depression Study were interviewed at baseline and at 18 months, and in the VDS also at 5 years. A general population comparison group (n=264) was surveyed by mail. RESULTS Compared with non-PD patients, PD patients scored lower on self-directedness and cooperativeness. Cluster B and C PDs associated with high Novelty Seeking and Harm Avoidance, respectively. In logistic regression models, sensitivity and specificity of Temperament and Character Inventory (TCI) dimensions for presence of any PD were 53% and 75%, and for specific PDs from 11% to 41% and from 92% to 100%, respectively. The 18-month test-retest correlations of TCI-R dimensions ranged from 0.58 to 0.82. CONCLUSIONS Medium-term temporal stability of TCI in a clinical population appears good. Character scores differ markedly between PD and non-PD patients, whereas temperament scores differ only somewhat between the specific PDs. However, the TCI dimensions capture only a portion of the differences between PD and non-PD patients.

Personality disorders and suicide attempts in unipolar and bipolar mood disorders.

BACKGROUND Comorbid personality disorders may predispose patients with mood disorders to suicide attempts (SAs), but factors mediating this effect are not well known. METHODS Altogether 597 patients from three prospective cohort studies (Vantaa Depression Study, Jorvi Bipolar Study, and Vantaa Primary Care Depression Study) were interviewed at baseline, at 18 months, and in VDS and PC-VDS at 5 years. Personality disorders (PDs) at baseline, number of previous SAs, life-charted time spent in major depressive episodes (MDEs), and precise timing of SAs during follow-up were determined and investigated. RESULTS Overall, 219 (36.7%) patients had a total of 718 lifetime SAs; 88 (14.7%) patients had 242 SAs during the prospective follow-up. Having any PD diagnosis increased the SA rate, both lifetime and prospectively evaluated, by 90% and 102%, respectively. All PD clusters increased the rate of new SAs, although cluster C PDs more than the others. After adjusting for time spent in MDEs, only cluster C further increased the SA rate (by 52%). Mediation analyses of PD effects on prospectively ascertained SAs indicated significant mediated effects through time at risk in MDEs, but also some direct effects. LIMITATIONS Findings generalizable only to patients with mood disorders. CONCLUSIONS Among mood disorder patients, comorbid PDs increase the risk of SAs to approximately two-fold. The excess risk is mostly due to patients with comorbid PDs spending more time in depressive episodes than those without. Consequently, risk appears highest for PDs that most predispose to chronicity and recurrences. However, also direct risk-modifying effects of PDs exist.

NEUROTICISM MEDIATES THE EFFECT OF P2RX7 ON OUTCOMES OF MOOD DISORDERS

We previously reported an association between P2RX7 variant rs208294, diagnosis, and the longitudinal course of mood disorders. Here, we test whether the personality trait neuroticism mediates the effect of P2RX7 on the course of mood disorders.

A single dose of mirtazapine attenuates neural responses to self-referential processing

Increased self-focus is a core factor in the psychopathology of depression. Cortical midline structures (CMS) are implicated in the neurobiology of self, depression and antidepressant treatment response. Mirtazapine, an antidepressant that increases serotonin and norepinephrine release, enhances processing of positive and attenuates processing of negative emotional information in healthy volunteers after a single dose. These early changes, which are opposite to the negative information bias in depression, may be important for the therapeutic effect of mirtazapine. It nevertheless remains unresolved whether/how mirtazapine specifically influences processing of self-referential emotional information. Half of the healthy volunteers (n=15/30) received a single dose of mirtazapine, in an open-label design, two hours before functional magnetic resonance imaging (fMRI), and the other half was scanned as a control group without medication. During fMRI the participants categorized positive and negative self-referential adjectives. Mirtazapine attenuated responses to self-referential processing in the medial prefrontal cortex and the anterior cingulate cortex. Mirtazapine further decreased responses to positive self-referential processing in the posterior cingulate cortex and parietal cortex. These decreased responses of the CMS suggest that mirtazapine may rapidly improve the ability of the CMS to down-regulate self-referential processing. In depressed patients, this could lead to decreased self-focus and rumination, contributing to the antidepressant effect.

Response style and severity and chronicity of depressive disorders in primary health care.

BACKGROUND Response styles theory of depression postulates that rumination is a central factor in occurrence, severity and maintaining of depression. High neuroticism has been associated with tendency to ruminate. We investigated associations of response styles and neuroticism with severity and chronicity of depression in a primary care cohort study. METHODS In the Vantaa Primary Care Depression Study, a stratified random sample of 1119 adult patients was screened for depression using the Prime-MD. Depressive and comorbid psychiatric disorders were diagnosed using SCID-I/P and SCID-II interviews. Of the 137 patients with depressive disorders, 82% completed the prospective five-year follow-up with a graphic life chart enabling evaluation of the longitudinal course of episodes. Neuroticism was measured with the Eysenck Personality Inventory (EPI-Q). Response styles were investigated at five years using the Response Styles Questionnaire (RSQ-43). RESULTS At five years, rumination correlated significantly with scores of Hamilton Depression Rating Scale (r=0.54), Beck Depression Inventory (r=0.61), Beck Anxiety Inventory (r=0.50), Beck Hopelessness Scale (r=0.51) and Neuroticism (r=0.58). Rumination correlated also with proportion of follow-up time spent depressed (r=0.38). In multivariate regression, high rumination was significantly predicted by current depressive symptoms and neuroticism, but not by anxiety symptoms or preceding duration of depressive episodes. CONCLUSIONS Among primary care patients with depression, rumination correlated with current severity of depressive symptoms, but the association with preceding episode duration remained uncertain. The association between neuroticism and rumination was strong. The findings are consistent with rumination as a state-related phenomenon, which is also strongly intertwined with traits predisposing to depression.